chr14-74407576-C-A

Position:

• chr14-74407576-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001105579.2(SYNDIG1L):​c.676G>T​(p.Val226Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYNDIG1L NM_001105579.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.16

Genes affected

SYNDIG1L (HGNC:32388): (synapse differentiation inducing 1 like) Predicted to be located in Golgi apparatus. Predicted to be integral component of membrane. Predicted to be active in intracellular membrane-bounded organelle and membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNDIG1L	NM_001105579.2	c.676G>T	p.Val226Leu	missense_variant	4/4	ENST00000331628.8	NP_001099049.1
SYNDIG1L	XM_017021600.2	c.676G>T	p.Val226Leu	missense_variant	4/4		XP_016877089.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNDIG1L	ENST00000331628.8	c.676G>T	p.Val226Leu	missense_variant	4/4	5	NM_001105579.2	ENSP00000331474.3
SYNDIG1L	ENST00000554823.1	c.676G>T	p.Val226Leu	missense_variant	3/3	3		ENSP00000450439.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 06, 2024

The c.676G>T (p.V226L) alteration is located in exon 4 (coding exon 3) of the SYNDIG1L gene. This alteration results from a G to T substitution at nucleotide position 676, causing the valine (V) at amino acid position 226 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;.
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	0.97	L;L
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.0	N;N
REVEL	Pathogenic	0.68
Sift	Benign	0.033	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		0.96	D;D
Vest4		0.69
MutPred		0.36		Gain of catalytic residue at V224 (P = 0);Gain of catalytic residue at V224 (P = 0);
MVP		0.86
MPC		0.96
ClinPred		0.95	D
GERP RS		4.8
Varity_R		0.27
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2086093176; hg19: chr14-74874279;